Anxiety is characterized by heightened response to threat. However, the precise etiologic basis of anxiety disorders remains obscure. Differing from prevailing amygdala-centric views of threat processing and anxiety pathophysiology, this application proposes a neurosensory account, highlighting a sensory pathway to anxiety. Based on accruing new evidence from our laboratory and other groups, we posit that the biological significance of a stimulus can be stored in the sensory system such that the affective value is decoded as soon as the input registers with the sensory brain, paralleling and often preceding limbic- based threat evaluation. As one of the first operations in the cognitive stream, biased sensory perception of threat can then influence downstream processes, directly or indirectly contributing to a variety of cognitive and emotional anomalies observed in anxiety. Representing one of the first lines of research on basic sensory processing of threat in anxiety, this program would provide new insights into basic threat analysis and anxiety genesis, and thus help to innovate clinical treatment for anxiety disorders. Towards that end, this proposal will employ a cognitive-affective neuroscience approach to firstly define sensory encoding of threat in anxiety with two conceptual emphases: 1) to accentuate highly specialized sensory representations of individual threat subtypes, which could inform the neural basis for distinct and sometimes contradictory responses and reflexes to different threats, and account for the heterogeneous symptomology of anxiety disorders (Specific Aim 1); and 2) to evaluate threat perception of multi- and cross-modal (vs. unimodal) sensory input, which, by optimally simulating real-life sensory experience, holds great promise for revealing novel multifaceted and modality-specific sensory biases of threat in anxiety (Specific Aim 2). Secondly, the planned research will mechanistically specify the impact of initial perceptual bias to threat on subsequent emotional and cognitive processes, giving rise to various anxiety symptoms (in particular, negative interpretation, excessive social avoidance and selective attention to threat; Specific Aim 3). In six independent experiments, we will employ a unique and fully developed constellation of expertise and techniques (functional magnetic resonance imaging, fMRI; brain event- related potentials, ERPs; autonomic physiology; psychophysics; and anxiety assessment and provocation) to determine the neural underpinnings of sensory perception of threat and its behavioral consequences, varying as a function of anxiety. The project findings will create a body of knowledge that is likely to challenge the dominant limbic-centered conceptualization of anxiety, promoting a shift to a multi-system, multi-path theorization. PUBLIC HEALTH RELEVANCE: Anxiety disorders are the most common psychiatric illness, causing a great deal of devastation and suffering for the patients. However, the etiology of anxiety remains obscure. Traditional accounts for anxiety genesis typically implicate exaggerated amygdala reactivity as the primary mechanism, but the proposal here points to a novel alternative-a neurosensory model of anxiety. The proposed investigation will elucidate aberrant sensory representation of threat in the sensory brain and consequent threat perception bias in anxiety, which intensifies and perpetuates anxiety symptoms directly or indirectly via its impact on downstream information processing. As such, this research program will generate significant new insights into anxiety etiology and greatly contribute to clinical prevention and intervention of this illness.